Bis-conjugation of Bioactive Molecules to Cisplatin-like Complexes through (2,2 '-Bipyridine)-4,4 '-Dicarboxylic Acid with Optimal Cytotoxicity Profile Provided by the Combination Ethacrynic Acid/Flurbiprofen

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Biancalana, L (Author) Other; Batchelor, LK (Author) Other; Pereira, SAP (Author) Other; Tseng, PJ (Author) Other; Zacchini, S (Author) Other; Pampaloni, G (Author) Other; Lucia L M F S Saraiva (Author) FFUP; Dyson, PJ (Author) Other; Marchetti, F (Author) Other

Journal

Title: Chemistry - A European Journal

ISSN: 0947-6539

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 2 Citations

Other information

Authenticus ID: P-00T-32H

DOI: 10.1002/chem.202003199

Abstract (EN): A facile route to Pt-II complexes doubly functionalized with bioactive molecules through a bipyridine-type ligand is described. Initially, ligands L-EE (containing two ethacrynic acid units), L-EF (ethacrynic acid+flurbiprofen) and L-EB (ethacrynic acid+biotin) were obtained in moderate to good yields from 2,2 '-bipyridine-4,4 '-dicarboxylic acid. Subsequent reaction of the ligands with [PtCl2(DMSO)(2)] afforded complexes [PtCl2(L-EE)] (2), [PtCl2(L-EF)] (3) and [PtCl2(L-EB)] (4) in high yields. All compounds were fully characterized by analytical and spectroscopic methods. Complexes 2-4 are highly stable in water/DMSO solution at 37 degrees C after 72 h, whereas progressive release of the bioactive fragments was detected in a cell culture medium. The compounds were assessed for their in vitro antiproliferative activity towards tumorigenic A2780, A2780cisR and Y79 cells and non-tumourigenic HEK293 cells. In particular, the combination of ethacrynic acid and flurbiprofen in 3 overcomes cisplatin-based resistance and provides strong cancer cell selectivity. Enzyme inhibition assays on human GST P1 and human COX-2 and cross-experiments with complex 1, analogous to 2-4 but lacking bio-groups, revealed a clear synergy between the Pt-II frame and the bioactive organic components.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12